tbuckley/cabot-search huggingface dataset:
Impact of tumor percentage on the assessment of homologous recombination deficiency score using a NGS 523 gene panel and a cytogenetic software in the evaluation of epithelial ovarian tumors.
Authors: Janira Navarro Sanchez, Zan Halford, Jason Kar Shing Pon, Amy M. Woron, Keith Y. Terada, Koah Vierkoetter, Christopher A. Lum
Journal: Journal of Clinical Oncology (2022)

e17567 Background: Platinum-taxane chemotherapy and surgical debulking are the optimal treatment for patients with advanced ovarian cancer. While initial response rates are above 80%, tumor recurrence occurs in about 70 to 80% of patients. Cells with defects in homologous recombination repair (HRR) are susceptible to cell death induced by Poly (ADP-ribose) polymerase inhibitors (PARPi). These drugs are used to treat recurrent neoplasms that have BRCA1 or BRCA2 mutations or homologous recombination deficiency (HRD). Low tumor percentage in test samples, which is common in clinical practice, is often overlooked when addressing HRD tests. The goal of this study was to determine the optimal tumor content rate needed to detect HRD changes. Methods: A total of sixteen ovarian neoplasms were studied. These samples were sequenced using Illumina TSO500 NGS and interpreted using NxClinical software 6.1. In all cases, HRD scores were evaluated. A score of ≥42 was determined to be HR-deficient and a score &lt; 42 was considered HR-proficient. We aimed to identify the optimal tumor percentage needed for detection of HRD alterations. HRD scores were calculated with tumor percentages of 70%, 60%, 40%, and 20%. Additionally, chemotherapy response scores (CRS) were available in 8 of 16 cases. We correlated the CRS with HRD scores. Results: In this project, visualization of a 523-gene cancer exome panel was shown to be 66.7% sensitive and 100% specific for detecting genomic scars (HRD score). 68.75% of cases showed low HRD score and 31.25% of cases showed a high HRD score. Next generation sequencing (NGS) results for most specimens are adequate with a tumor content rate of 70%. CRS1 cases were HR-proficient. For CRS2 and CRS3 we had mixed results. Conclusions: HRD correlates with platinum sensitivity in epithelial ovarian tumors, which has clinical significance as a predictor of sensitivity to PARPi. During treatment, tissue samples are obtained at different times points and sources, some at diagnosis/surgical debulking and some after neoadjuvant therapy. After neoadjuvant treatment, tumor volume is reduced. Cytology specimens are convenient for obtaining tumoral cells, but tumor volumes are usually small. Profiling tumors of low volume decrease the chances of detecting a patient’s eligibility for targeted maintenance. Our next steps will evaluate the performance of tissue microarrays using the Infinium CytoSNP-850K array compared to NGC cytogenomics at low tumor volumes.
Real-world data comparing atezolizumab plus taxane therapy versus taxane alone as first-line treatment of metastatic triple-negative breast cancer patients in the United States.
Authors: Dvir Aran, Avital Klein-Brill, Michael Jordan Fisch, Shlomit Amar-Farkash
Journal: Journal of Clinical Oncology (2022)

e18767 Background: A recent clinical trial (Impassion131) showed that addition of atezolizumab to paclitaxel does not provide survival benefit for first-line (1L) treatment of metastatic triple-negative breast cancer (mTNBC) patients. The study was in contradiction to a previous study (Impassion130) that did show benefit using atezolizumab plus nab-paclitaxel. Using real-world data, we evaluated the impact on overall survival and post-treatment hospitalizations of 1L Atezolizumab + Taxane (Nab-Paclitaxel) (A+T) vs. Taxane agents alone (Paclitaxel or Nab-Paclitaxel) (T) in individuals with mTNBC. Methods: We performed a retrospective cohort study of 1L mTNBC patients between 1/2016 and 6/2021, utilizing administrative claims data from the Anthem Cancer Care Quality Program. Real-world overall survival (rwOS) was defined as time from diagnosis to death. Cox model with inverse probability of treatment weighting was used to adjust for age, ECOG, Socioeconomic deprivation index (SDI), comorbidity, and liver and bone metastatic sites. Median rwOS was estimated using the weighted Kaplan-Meier method. Adjusted hazard ratios (aHR) were estimated using weighted Cox proportional hazards models. We do not adjust for PD-L1 levels shown to have association with improved OS regardless of treatment, therefore, unlikely to confound our results. Results: The A+T combination therapy became a preferred 1L type of treatment for mTNBC patients since its introduction in 2019. We identified 155 (55%) individuals with 1L mTNBC who received A+T and compared this cohort to 128 (45%) individuals who received T alone. The A+T group were younger and had lower proportion of bone metastatic sites (Table). Percentage of patients with previous chemotherapy in the last year was similar between the groups (p = 0.9). Median rwOS was 13.6 and 17.5 months, in A+T and T group, respectively (p = 0.2). In adjusted survival analysis, the addition of atezolizumab showed insignificant increase in the risk of mortality (aHR: 1.09 (0.74-1.61), p = 0.66). Our post-treatment analysis did not identify statistically significant differences between the groups, in terms of post-treatment hospitalizations, adverse events classes, or length of stay of hospitalized patients. Conclusions: Our retrospective cohort study demonstrated that the addition of atezolizumab to 1L treatment, was not associated with survival benefit or reduce post-treatment adverse events in mTNBC patients.[Table: see text]
S1314 correlative analysis of ATM, RB1, ERCC2, and FANCC mutations and pathologic complete response (pT0) at cystectomy after neoadjuvant chemotherapy (NAC) in patients with muscle invasive bladder cancer (MIBC): Implications for bladder preservation.
Authors: Elizabeth R. Plimack, Catherine Tangen, Melissa Plets, Rutika Kokate, Joanne Xiu, Chadi Nabhan, Eric A. Ross, Erin Grundy, Woonyoung Choi, Colin P.N. Dinney, I-Ling C. Lee, Scott Lucia, Thomas W. Flaig, David James McConkey
Journal: Journal of Clinical Oncology (2022)

4581 Background: SWOG S1314 (NCT02177695) was designed to validate the CoXEN classifier as a predictive biomarker in pts undergoing cystectomy after NAC. We repurposed banked DNA samples and prospective trial data from S1314 to further validate the predictive ability of the Philadelphia 4 gene signature (P4GS: any mutation in ATM, RB1, FANCC, ERCC2) to predict pT0 as previously reported (PMID: 26238431) and used in the RETAIN trial (NCT02710734). The RETAIN trial prospectively enrolled pts to receive NAC (DDMVAC) followed by allocation to bladder observation vs. intervention (cystectomy or RT) based on clinical evaluation and presence vs absence of P4GS. The primary objective of this correlative investigation was to determine whether presence of P4GS is predictive of pT0 at surgery. Methods: Eligibility for S1314 included cT2-T4a N0 M0 MIBC, cisplatin eligible, with plan for cystectomy; 237 pts were randomized between ddMVAC and gem/cis (GC) using standard dose/schedule. Of 167 pts who were evaluable for the original COXEN analysis (received 3+ cycles of chemo and evaluable for path response) adequate banked DNA was available for 105. Next-generation sequencing using the CARIS 592 Gene Panel (Caris Life Sciences, Phoenix, AZ) was performed. Pathogenic mutation or VUS of ATM, RB1, FANCC or ERCC2 was noted as present or absent for each pt and correlated with pT0 using logistic regression, adjusting for clinical stage. Results: Among the 105 pts, 51% ddMVAC, 49% GC. 15% female, 95% white, 15% clinical stage T3/T4a Prevalence of mutations: ATM (24%), ERCC2 (17%), FANCC (4%), RB1 (24%) and any variant 53%. Presence of any mutation correlated with pT0 (p = 0.0006), sensitivity 79%, specificity 59%. This association did not vary by treatment arm (MVAC vs. GC). The table below shows the contributions of each of the 4 genes with the greatest contribution from ATM and ERCC2. FANCC was non-contributory due to low prevalence. Conclusions: Patients with a mutation in ATM, RB1, FANCC or ERCC2 (P4GS) have a statistically significantly higher odds of a pT0 with GC or MVAC compared to those who do not have any variant. This signature was used to prospectively allocate patients to bladder observation as part of the RETAIN trial previously reported (ASCO GU 2021). RETAIN completed enrollment, final analysis of the primary endpoint – 2-year metastasis free survival – is expected later in 2022. Clinical trial information: NCT02177695.
A phase I clinical trial of trametinib in combination with TAS-102 in patients with chemotherapy-resistant RAS-mutated (PIK3CA/PTEN-wild type) metastatic colorectal cancer.
Authors: Jeremy Chuang, Jun Gong, Sierra Li, Chongkai Wang, Marwan Fakih
Journal: Journal of Clinical Oncology (2022)

e15579 Background: TAS-102 was approved in 2015 after the phase III RECOURSE clinical trial demonstrated a modest improvement in overall survival in refractory metastatic colorectal cancer (mCRC). Preclinical models have shown synergistic activity between MEK inhibitors and TAS-102 in RAS-mutant (MT) and PIK3CA/PTEN wild-type (WT) models . We conducted a phase I study of trametinib plus TAS-102 in this molecularly selected refractory metastatic colorectal cancer patient population to explore the safety and efficacy of this combination. Methods: A 3+3 dose de-escalation single arm phase I clinical trial was performed in patients with mCRC who progressed on prior standard therapies but with no prior TAS-102 exposure. Patients received fixed dosing of trametinib 2mg oral daily along with de-escalating doses of TAS-102 beginning at 35 mg/m 2 twice daily on days 1-5 and days 8-12 every 28 days. The primary endpoint of this study was to evaluate the maximum tolerated dose (MTD). Secondary objectives included an assessment of safety and toxicity of the combination regimen by CTCAE version 4.0 and any evidence of clinical activity including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) with this combination per RECIST guideline 1.1. Results: Between March 21, 2018, to March 19, 2020, 25 eligible patients were enrolled in this study. MTD was determined to be TAS-102 35 mg/m 2 orally twice daily on days 1-5 and days 8-12 every 28 days with continuous trametinib dosing at 2mg orally daily. No patients achieved a partial or complete response. 5 of 21 evaluable patients (23.81%) achieved a stable disease response. Median PFS was 2 months (95% confidence interval (CI) 1.70-4.82) while median OS was 7 months (95% CI 6.36-11.48). Treatments were well tolerated with most common grade ≥ 3 adverse events being anemia (20%), neutropenia (12%), leukopenia (8%), diarrhea (8%), rash (4%), and fatigue (4%). Conclusions: Trametinib in combination with TAS-102 demonstrated a manageable safety profile however did not achieve meaningful clinical benefit in patients with RAS-MT and PIK3CA / PTEN-WT refractory mCRC. Research sponsor: Novartis. Clinical trial information: NCT03317119.
Impact of molecular features on outcome in African American or Black women with type 1 endometrial cancer.
Authors: Roy Khalife, So Hyeon Park, Stephanie Erickson, Genevra Magliocco, Anthony Martin Magliocco
Journal: Journal of Clinical Oncology (2022)

5597 Background: Among women with endometrial cancer (EC), African American or Black (AAoB) population share a disproportionate burden of cancer deaths. Previous research exploring genetic and molecular explanations revealed White (W) women with EC are more likely to have mutations in PTEN, while AAoB women have higher rates of mutations in p53. However, these studies did not stratify EC by subtype, which occur at different rates among racial groups. Here, we aim to focus on molecular differences between racial groups, specifically in Type 1 EC (T1EC). Methods: Molecular data from TCGA Uterine Corpus Endometrial Carcinoma datasets on cBioPortal was used. Cancer type was filtered to Uterine Endometrioid Carcinoma Type 1 and separated by race. A total of 711 cases were analyzed for gene alterations, expression versus copy number variations, survival curves, and OncoPrints; significant findings and differences between racial groups were noted. The Surveillance, Epidemiology, and End Results (SEER) database was used to access the frequency, rate, and survival of AAoB and W with EC. Results: The genes analyzed on cBioPortal (575 W, 136 AAoB) depicted a similar alteration rate between the two groups, except for the most altered gene, PTEN (66% altered in W, 38% in AAoB). W women with a PTEN and PIK3CA alterations had significantly increased 5-year survival periods (P-value = 1.573e-3), while these alterations had no effect survival in AAoB. Six of the ten most altered genes between the two subgroups, and 6 of the 17 most actionable genes, were statistically significant for W but not for AAoB. SEER analyses depicted a frequency of 51,677 W and 3,915 AAoB, with a rate of 5.7% and 3.9%, respectively. The observed survival was 96.1% after 1 year and 85.6% after 5 years for W, compared to 92.8% after 1 year and 76.9% after 5 years for AAoB. Conclusions: Based on 5 years of data, overall survival (OS) rates among W women with T1EC are better than AAoB. PTEN mutation confers a survival advantage in W but not in AAoB, indicating that in AAoB, PTEN may play a different role or other factors may override the PTEN advantage. Additional analyses revealed non-remarkable findings, suggesting that molecular factors play a minor role in T1EC disparities or that a larger AAoB sample size is necessary. A better understanding of the downstream signaling pathways of common mutations in T1EC is necessary to further elucidate factors that contribute to racial disparities in T1EC. [Table: see text]
Smoking and COVID-19 in patients with cancer: Novel analysis from CCC19 registry.
Authors: Amit Kulkarni, Cassandra Hennessy, Grace Wilson, Vidhyalakshmi Ramesh, Clara Hwang, Joy Awosika, Ziad Bakouny, Diana Vilar-Compte, Hina Khan, Rana R. McKay, Chinmay Jani, Matthew Puc, Anup Kasi, Stephanie A. Berg, Dan Ran Castillo, Brandon M. Hayes-Lattin, Wylie Hosmer, Daniel Blake Flora, Narjust Duma
Journal: Journal of Clinical Oncology (2022)

e18766 Background: Patients (pts) with thoracic cancers have a high rate of hospitalization and death from COVID-19. Smoking has been associated with increased risk for severe COVID-19. However, there is limited data evaluating the impact of smoking recency on COVID-19 severity in pts with cancer. We aimed to characterize the clinical outcomes of COVID-19 based on the recency of smoking in pts with thoracic cancers (TC) and all other cancers (OC). Methods: Adult pts with cancer and lab-confirmed SARS-CoV-2 and smoking history recorded in the CCC19 registry (NCT0435470) were included. Pts were stratified by cancer type (TC or OC) and further stratified into subgroups based on the recency of smoking cessation: current smoker; former smokers who quit &lt; 1 yr. ago; 1-5 yr. ago; 6-10 yr. ago; quit &gt; 10 yr. ago; and never smoker. 30-day all-cause mortality was the primary endpoint. Secondary endpoints were any hospitalization; hospitalization with supplemental O2; ICU admission; and mechanical ventilation. Results: From January 2020 to December 2021, 752 pts from TC group and 8,291 pts from OC group met the inclusion criteria. 78% of patients in TC group ever smoked compared to 36% patients in the OC group. In both groups, the majority of never-smokers were females (70% and 60% in TC and OC respectively). The burden of smoking and the rate of pulmonary comorbidities (PC) was higher in the TC group (PC 22-69%) compared to OC group (PC 12-26%) across all smoking strata. Overall, 30-day all-cause mortality was 21% and 11% in pts with TC and OC respectively. Former smokers who quit &lt; 1 year ago in TC group had the highest rate of mortality and severe COVID-19 outcomes. However, in the OC group, there was no consistent trend of higher mortality or severe COVID-19 outcomes in specific subgroups based on smoking recency. Conclusions: To our knowledge this is the largest study evaluating the effect of granular phenotypes of smoking recency on COVID-19 outcomes in pts with cancer. Recent smokers who quit &lt; 1 year ago in TC group had the highest rate of mortality and severe COVID-19. Further analysis exploring the factors (e.g., smoking pack years) associated with severe outcomes in this subgroup is planned.[Table: see text]
A phase Ia/Ib study of intrathecal deferoxamine in patients with leptomeningeal metastases.
Authors: Jessica Wilcox, Lisa R. Modelevsky, Tiffany Thomas, Serge Cremers, Robert J. Young, Anne S. Reiner, Katherine Panageas, Helena Alexandra Yu, Adrienne Ann Boire
Journal: Journal of Clinical Oncology (2022)

TPS2074 Background: Leptomeningeal metastases (LM) represent an aggressive form of advanced cancer with few durable therapeutic options. One of the principal barriers in treating LM is the paucity of knowledge on cancer cell survival and proliferation within the nutrient-sparse cerebrospinal fluid (CSF). Single-cell RNA sequencing of patient-derived CSF has identified that cancer cells in the spinal fluid employ the single iron-binding transporter and receptor system, lipocalin-2/SLC22A17, to gather sparse iron to sustain their metabolic needs. This phenotype is recapitulated in preclinical mouse models of LM. Depletion of CSF iron via intracisternal administration of deferoxamine, a parenteral iron chelator, dramatically reduced LM growth and significantly prolonged survival in preclinical models. Exploiting LM iron dependency using intrathecal deferoxamine (IT-DFO) represents a novel therapeutic approach for patients with LM. Methods: This is a prospective, open-label, single center phase Ia dose escalation study of IT-DFO in patients with LM from any solid tumor malignancy to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D), followed by a phase Ib dose expansion of IT-DFO at the RP2D in patients with LM from non-small-cell lung cancer (NSCLC). Eligibility criteria include newly diagnosed or recurrent LM identified by magnetic resonance imaging (MRI), positive CSF cytology, and/or elevated CSF circulating tumor cells (CTCs), age ≥ 18 years, Karnofsky Performance Status ≥ 60, and life expectancy ≥ 8 weeks. All patients will receive IT-DFO in 28-day cycles at a frequency of twice weekly (cycle 1), once weekly (cycle 2), and once every two weeks (cycle 3+). Patients will be monitored for LM progression by neurological examination, neuraxial MRI, and CSF cytology as per modified Response Assessment in Neuro-Oncology LM criteria. Phase Ia will involve a modified accelerated titration over 9 dosing cohorts (IT-DFO dose range 10mg to 495mg) with monitoring for dose-limiting toxicities until the MTD is reached. Phase Ib will further explore the safety of IT-DFO at the RP2D in 20 patients with NSCLC LM. Secondary objectives include the determination of pharmacokinetic and pharmacodynamic properties of IT-DFO and its metabolite, ferrioxamine, in the CSF and serum (phase Ia/Ib), and efficacy outcomes (phase Ib) including LM-objective response rate, LM-clinical benefit rate, LM-duration of response, LM-progression-free survival, and overall survival. Exploratory analyses will prospectively correlate CSF CTC enumeration with treatment response and characterize the impact of IT-DFO on cancer cell metabolism, resistance pathways, and the CSF immune microenvironment. Clinical trial information: NCT05184816.
A multivariate logistic model to predict odds of small bowel cancer by various risk factors.
Authors: Diana Franco, Umer Farooq, Mohammad Ebad Ur Rehman, Irene Ma
Journal: Journal of Clinical Oncology (2022)

e16307 Background: Small bowel cancer (SBC) is a rare malignancy, and current epidemiologic literature consists of small single-center studies describing various etiologic associations. Therefore, we evaluated the strength of association of various SBC risk factors using a nationally representative patient sample. Methods: We investigated the National Inpatient Sample 2019 employing International Classification of Diseases-10 (ICD-10) codes to include adult patients with SBC. Odds of SBC were tested for various risk factors individually using univariate logistic regression. In addition, a multivariate regression model was developed to test the odds of developing SBC while controlling for all other risk factors. Analyses were performed using STATA (v 14.2), considering 2 sided P&lt; 0.05 as statistically significant. Results: Out of 30,200,000 adult hospitalized patients in 2019, 9,629 had a diagnosis of SBC. Each one-year increase in age predicted a 4% increased odds of SBC. Males had 28% higher odds compared to females. Compared to whites, Blacks and Asians had higher odds of SBC while Hispanics did not. Smoking, alcohol, HIV, and low socioeconomic status were associated with higher odds of SBC while controlling for all other risk factors ( P &lt; 0.05). Disorders of lipid metabolism, hormone replacement therapy, prior cholecystectomy, celiac disease were associated with lower odds. Crohn’s disease, familial adenomatous polyposis (FAP), and Lynch syndrome were not significantly associated with higher odds of SBC ( P &gt; 0.05). Conclusions: FAP and Lynch syndrome appear to increase the risk of polyp formation in the small intestine but not SBC. The lower odds mentioned for certain variables are merely an association and do not imply a protective effect. The reliance on ICD-10 codes and the inability to distinguish between various cancer subtypes limits our conclusion and needs to be addressed in future studies.[Table: see text]